Study Results
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Basic Information
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UNKNOWN
6839 participants
OBSERVATIONAL
1998-12-31
2021-01-31
Brief Summary
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There is so far no data on possible long-term effects following years of such B-vitamin treatment.
Thus, the main objective of the combinded NORVIT-WENBIT study will will be to evaluate the long-term effect of the B-vitamin intervention on incident life-style diseases including cardiovascular disease, diabetes, osteoporotic fractures and cancer.
A secondary object will be the identification of risk phenotypes or genotypes, and if such risk associations are midified by the B-vitamin intervention
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Detailed Description
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Two large B-vitamin intervention trials have been performed in Norway during the period 1998 to 2005, NORVIT and WENBIT, both registered at ClinicalTrials.gov, identifiers NCT00266487 and NCT00354081, respectively. The main objective in these trials was to study the effects of homocysteine-lowering therapy with folic acid and vitamin B12 to reduce the risk of cardiovascular events in patients with established coronary artery disease. The B-vitamin intervention, which included vitamin B6 in a 2x2 factorial design, was identical in the two trials. Follow-up was terminated for NORVIT on March 31st 2004 and for WENBIT October 5th 2005. Results from the NORVIT trial was published April 2006 {Bonaa, 2006} and preliminary results from the WENBIT trial were presented at the annual congress of the European Society of Cardiology September 4th 2007 {Zegers, 2007}. The WENBIT trial is completed and submitted for publication early in year 2008.
So far, none of the B-vitamin intervention trials have shown any statistically significant favourable effect of homocysteine-lowering therapy with folic acid with or without concomitant vitamin B12 on cardiovascular events {Bazzano, 2006}. In NORVIT there was even a trend towards an increased risk of cardiovascular events (myocardial infarctions) in patients receiving the combination of folic acid, vitamin B12 and vitamin B6. This trend was not observed in WENBIT. However, the treatment with folic acid / B12 was associated With a more rapid progression of angiographic coronary atenoses {Løland, 2010}. Thus, the "homocysteine-hypothesis" of vascular disease has been attenuated through the emergence of these negative trial results, whereas a potential harmful effect of the B-vitamin intervention has been revealed.
There is so far no data on possible long-term effects following years of B-vitamin supplementation. By combining analyses and follow-up in the NORVIT and WENBIT cohorts, we will probably have some more answers both considering possible subgroup and long-term effects of the B-vitamin intervention.
Current data indicate that folate prevents cancer, especially breast and colorectal cancer. However, during the last few years several reports have challenged this assumption. Swedish observational studies found increased risk of colorectal cancer at high blood folate levels {Van Guelpen, 2006} and increased risk of prostate cancer at high levels of folate and vitamin B12 {Hultdin, 2005}. In a randomised trial with folic acid versus placebo to prevent colorectal adenomas, one found increased risk of cancer in the group receiving folic acid, especially of prostate cancer {Cole, 2007}. In a long-term follow-up of women taking high doses of folic acid throughout pregnancy one found a doubled risk of deaths attributable to breast cancer {Charles, 2004}. Recently it has been hypothesized that the implementation of folic acid fortification of foods may have been wholly or partly responsible for the observed increase in colorectal cancer rates in the USA and Canada in the mid to late 1990s {Mason, 2007}. This has led to new hypotheses that folate may prevent carcinogenesis but may enhance the growth of established cancer cells {Ulrich, 2007}. The question of possible adverse effects of folic acid supplementation will be of major importance when public health administrations decide whether to implement or enhance programs folic acid fortification of foods.
The effect of the B-vitamin intervention will also be studied in relation to other life-style diseases like diabetes and osteoprosis.
Additionally, the combined NORVIT-WENBIT cohort will used for observational studies evaluating new risk phenotypes or genotypes and their potential effect modification by the B-vitamin interventions.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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1
Participants in NORVIT and WENBIT allocated to daily oral treatment with folic acid 0.8 mg and vitamin B12 0.4 mg
No interventions assigned to this group
2
Participants in NORVIT and WENBIT allocated to daily oral treatment with folic acid 0.8 mg, vitamin B12 0.4 mg and B6 40 mg.
No interventions assigned to this group
3
Participants in NORVIT and WENBIT allocated to daily oral treatment with vitamin B6 40 mg.
No interventions assigned to this group
4
Participants in NORVIT and WENBIT allocated to daily oral treatment with placebo
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
Exclusion Criteria
27 Years
86 Years
ALL
No
Sponsors
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University of Tromso
OTHER
Norwegian Foundation for Health and Rehabilitation
OTHER
Haukeland University Hospital
OTHER
Responsible Party
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Ottar Kjell Nygård
MD, PhD
Principal Investigators
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Ottar Nygård, MD, PhD
Role: STUDY_CHAIR
Department of Heart Disease, Haukeland University Hospital
Locations
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Department of Heart Disease, Haukeland University Hospital
Bergen, , Norway
University of Tromsø
Tromsø, , Norway
Countries
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References
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Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006 Apr 13;354(15):1578-88. doi: 10.1056/NEJMoa055227. Epub 2006 Mar 12.
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006 Dec 13;296(22):2720-6. doi: 10.1001/jama.296.22.2720.
Clarke R, Armitage J, Lewington S, Collins R; B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of vascular disease: protocol for a collaborative meta-analysis. Clin Chem Lab Med. 2007;45(12):1575-81. doi: 10.1515/CCLM.2007.346.
Van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E, Winkvist A, Palmqvist R. Low folate levels may protect against colorectal cancer. Gut. 2006 Oct;55(10):1461-6. doi: 10.1136/gut.2005.085480. Epub 2006 Apr 25.
Hultdin J, Van Guelpen B, Bergh A, Hallmans G, Stattin P. Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study. Int J Cancer. 2005 Feb 20;113(5):819-24. doi: 10.1002/ijc.20646.
Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER; Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 Jun 6;297(21):2351-9. doi: 10.1001/jama.297.21.2351.
Charles D, Ness AR, Campbell D, Davey Smith G, Hall MH. Taking folate in pregnancy and risk of maternal breast cancer. BMJ. 2004 Dec 11;329(7479):1375-6. doi: 10.1136/bmj.329.7479.1375. No abstract available.
Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1325-9. doi: 10.1158/1055-9965.EPI-07-0329.
Ulrich CM, Potter JD. Folate and cancer--timing is everything. JAMA. 2007 Jun 6;297(21):2408-9. doi: 10.1001/jama.297.21.2408. No abstract available.
Ebbing M, Bleie O, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, Refsum H, Pedersen EK, Nygard O. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008 Aug 20;300(7):795-804. doi: 10.1001/jama.300.7.795.
Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njolstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009 Nov 18;302(19):2119-26. doi: 10.1001/jama.2009.1622.
Ulvik A, Ebbing M, Hustad S, Midttun O, Nygard O, Vollset SE, Bonaa KH, Nordrehaug JE, Nilsen DW, Schirmer H, Ueland PM. Long- and short-term effects of tobacco smoking on circulating concentrations of B vitamins. Clin Chem. 2010 May;56(5):755-63. doi: 10.1373/clinchem.2009.137513. Epub 2010 Mar 18.
Ebbing M, Bonaa KH, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njolstad I, Nilsen DW, Refsum H, Tverdal A, Vollset SE, Schirmer H, Bleie O, Steigen T, Midttun O, Fredriksen A, Pedersen ER, Nygard O. Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials. J Intern Med. 2010 Oct;268(4):367-82. doi: 10.1111/j.1365-2796.2010.02259.x.
Zuo H, Svingen GFT, Tell GS, Ueland PM, Vollset SE, Pedersen ER, Ulvik A, Meyer K, Nordrehaug JE, Nilsen DWT, Bonaa KH, Nygard O. Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles. J Am Heart Assoc. 2018 Apr 12;7(8):e008190. doi: 10.1161/JAHA.117.008190.
Related Links
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NORVIT on ClinicalTrials.gov
WENBIT on ClinicalTrials.gov
Other Identifiers
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REK-267.07
Identifier Type: OTHER
Identifier Source: secondary_id
DT-08/00230-2/RVB
Identifier Type: OTHER
Identifier Source: secondary_id
Hdir-08/623-
Identifier Type: OTHER
Identifier Source: secondary_id
NSD-17895
Identifier Type: -
Identifier Source: org_study_id
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